CA1045115A

CA1045115A - Process for preparing 6-aminopenicillanic acid, 7-aminocephalosporanic acid and derivatives

Info

Publication number: CA1045115A
Application number: CA232,939A
Authority: CA
Inventors: Ernesto Oppici; Anacleto Gianantonio
Original assignee: Gruppo Lepetit SpA
Current assignee: Gruppo Lepetit SpA
Priority date: 1974-08-07
Filing date: 1975-08-06
Publication date: 1978-12-26
Also published as: BE832218A; DK357575A; ZA754609B; FR2281367B1; JPS5141384A; NL180218B; FI66617B; HU170295B; JPS6131113B2; DD120445A5; IL47868A; NO151747B; CS183813B2; FI752191A; GB1467355A; FI66617C; NO752748L; FR2281367A1; NO151747C; SE7508880L

Abstract

ABSTRACT
It is known to hydrolyze, using protective groups, under strictly controlled reaction conditions the acylamino groups of -6 or -7 substituted penicillins or cephalosporins, respectively. However due to the reactive nature of these substances, generally the yields are low. Further more the protective groups are costly. Thus this the known reactions are unsuitable for industrial processes. The present invention over comes this problem by provid-ing a novel process for the hydrolysis of -6 or -7 substituted penicillins, cephalosporins and -3 substituted cephalosporins where in the protective group is an oxalyl halide, which substances are commercially available at a low price and not dangerous to handle.

Description

~L~)45~L~5 The present invention is concerned with a new and useful method for splitting the group R-CO from compounds of the general formula R-CO-NH ~ S
l ¦ D
oJ~J ::
~H3 - .
wherein D ma~ be the group ~

I CH3 ~

/ ~ COOM ~ ~ .

CH --or the group 1 2 .:
~ -CH2-X

`''''"'': "
COOM
.:
In these groups the carbon atom bearing the substituent COOM is linked to the nitrogen atom of the ~ -lactam ring. ~ .
When D represents the group :

~ CH3 \ C / ; ' CH
~ OOM
the compounds of the formula I are 6-acylaminopenicillanic acid derivatives of .. . ... .
formula '' ~; .

~()4S1~5 .. ;
,: ,., R-CO-NH I ~ CR II

- CH -O ~ COOM
and when D represents the group ; ''. ' !' ,'," ~' ''~' H2 , :' ':
ol ,..... .
~ H2 ~ :, C '~/ '' ' ' " ' ' ~i' , COOM
the compounds of formula I are 7-acylaminocephalosporanic acid derivatives of formula ~'' '' .:' S .:
R-CO-NH ¦ ~ H2 ~ : .
¦ I III .: . -O ~ N ~ ~ C-CH2-X

COOM ~ -: It is~known~from literature (Cephalosporins and Penicillins, chapter

2, page 27, Academic Press, New:~ork and London, 1972), that the hydroIisis of the acy1amino group at the 6- or 7- positionj of penicillins or cephalos-:~ 10 porins, respectively~ is quite a difficult~problem which requires strictly :- controlled reaction conditions, as owing to the lability of ~he subst~ates ~-many undesirable~side-reactions~may take place. Direct acid h~drolisis of cephalosporins~C or benzylpenicillin &S recovered from fermentation broths s practica11~ unsuccess~ful or gives very poor overall yields (lower than 1%).
On~the other handj~usefu1 procedures for hydrolizing the acylamino groups at ;.~ -ths~6- or 7-positions,:which can be employed on an industrial scale, are -2- ;

10453L~5 desirable as 6-aminopenicillanic acid, 7-aminocephalosporanic acid or its -derivatives at the 3-position are very important intermediate products for preparing manr "semi-synthe~ic" penicillins and cephalosporins with useful antimicrobial properties.
A general method for the cleavage of the amidic bond of penicillin deriving substrates and cephalosporins derivatives is that described in Belgian Patent 628.494; which comprises the following steps:
a) transformation of the amidic group into iminohalide;
b) subsequent transformation of the iminohalide into iminoether;
c) hydrolytic cleavage of the iminoether.
The Belguim process may provide 6-aminopenicillanic acid, 7-amino-cephalosporanic acid or its derivatives with ~arious substituents at the 3~
position in good yields owing tb the mild conditions which do not alter the heterocyclic system. However, this occurs only if the carboxy group on the heterocyclic portion of the selected substrate is blocked by an appropriate protecting agent, to avoid its transformation into carbonyl halide during formation of the iminohalide. It is therefore clear that the essential reaction which permits the desired end products to be obtained in good yields is the initial protection of the carboxylic group. It is understand-able that the choice of the appropriate protecting agent is rather criticalto the known process. Several methods for protecting the carboxy group on the heterocyclic portion of penicillin or cephalosporin derivatives are described in the literature, but none of them is devoid of practical disad-vantage, so that the so far known processes for preparing 6-amdnopenicillanic or 7- ainocephalosporanic acid, or the derivatives at the 3-position of 7-aminocephalosporanic acid present several difficulties when carried out on industrial scale.
The protection of the carbox~l group on the het~ocyclic portion of the substrate by formation of esters both organic and inorganic, is described in United States Patent 3,697,515.

-3-1~45~5 ::
Subsequent hydrolysis of the 6 or 7-acylamino group according to Belgian Patent 628,494 affords the desired acids in the form of the corresponding organic or inorganic esters. These esters are generally stable under the reaction conditions for hydrolizing the intermediate iminoethers.
To obtain the corresponding free acids it is necessary to submit the resulting esters to further treatments which may involre acidic or basic hydrolysis, hydrogenolysis or photolysis. These reactions generally occur under quite drastic conditions, which are disadvantageous to penicillins and cephalosporins due to the lability of the heterocyclic system. These result in procedures the formation of unwanted by products and consequently low overall yields. The blocking of the carboxy group by formation of silyl esters as described in United States Patents 3,499,909 and 3,575,9~0 repre- -sents a remarkable improvement ouer the method described in the previously cited United States Patent, but has considerable disadvantages as well~ which are essentially due to the nature of the protecting agents. In fact the haloalkylsylanes~ al4ylsilazanes or the analogous silicon derivatives which are employed as protecting groups of the carboxy function must be handled with extreme -caution being inflammable substances. The step concerned with the protection has to be carried out under rigorous anhydrous con~ditIons ;
as the blocking agents are very moisture-sensitive and are rapidly destroyed by traces of water, Furthermore,;*he application on an industrial scale of a process ;
involving as the first step the reaction of a carboxylic ~unction with silanes or sila~anes is not convenient, as the protecting agents are so exp~nsive, that the cost of the final products is considerably effected.
This is~accentuated if the penicillins or cephalosporins deriving substrates employed contain other functions, such as, amino, hydrox~, sulfhydryl or another~group which also re~uire protection in order to avoid undesirable side-reactions. Therefore, the silyl ester method is not very flexible, as it req~ires a critical selection of the starting penicillin or cephalosporin ' ~ '.'':

lV45~L1S ~ ~
substrate.
All these drawbacks are removed when, according to the present in-vention, the carboxy group on the heterocyclic portion of the substra.~e is reacted with an oxalyl halide, such as, oxalyl chloride or oxalyl bromide, at a temperature at which oxalyl halides surprisingly act as protecting agents, whereby the carbox~ group is transformed into the moiety COO-COCOhal, --where hal stands for a halogen atom, preferably bromine or chlorine~
The present invention provides a process for preparing 6-aminopenic-illanic acid~ 7-aminocephalosporanic acid and derivatives at-the 3-position of 7_aminocephalosporanic acid, and base addition salts thereof of the general formula S ' "'. ~
H2N ~D1 :

~ ~ ' ', wherein D1 may be the group \ /
C \
¦ CH3 CH

/ \ COOM
or the group9H2 ` ' .
,, ~Z,C --CH2-X
C
COOM .

in which the carbon atom bearing the carboxy group is linked to the nitrogen -:
: . .
atam of the ~ -lactam~ring, and M represents hydrogen, or metal or ammonium ; cations, X represents hydrogen, hydroxy, sulfhydryl, halo, a~ido, cyanog ~.

(C1 6) aIkoxy, (C2 6) alkanoyloxy, carbamoyloxy, (C1 6) alkylcarbamoyloxy, 1~)4S~15 aryloxy, aralkyloxy, aroyloxy, arylakanoyloxy wherein the aromatic portion is represented by a phenyl or naphthyl radical optionally substituted with (Cl_4) aIkyl, (Cl_4) alkoxy, halo and nitro groups and the alkyl or alkanoyl portions contain from 1 to 4 carbon atoms, tri-(Cl_4)-alkylammonio, pyridinio, (C1 4) alkyl substituted pyridinio, a group -S-Y or -S~ _Y wherein Y repre-sents (Cl 6) alkyl, (C2 6) alkanoyl~ a~yl and aralkyl as above defined~ a :~
5-7 membered heterocyclic ring containing 0, N and S and optionally ;
substituted with (Cl 4) alkyl~ hydroxy, hydroxy (Cl 4) alkyl or trifluoro-methyl, which comprises reacting a molar proportion of a substrate of the general formula . :. ' S , R-CO~NH ~ ~
10 l , II
J ' -or an acid salt thereof, wherein R is selected from: .
a) an alkyl group of 2 to 8 carbon atoms; :~
b) a group MOOC ~ H -(CH2)3, wherein M is defined as ' 11 . :.
above and R1 is hydrogen, amino or a protected amino group; .
c) a group ~ W-(CH2)m wherein W represents 0, S or a carbon_ carbon bond, and m is an integer from O to 3~ with the -pro~s~. that when W is oxygen or sulfur, m is different from zero;
d) a group ~ wherein Q stands for hydrogen, hydroxy or ~ . ~
~ H- :

6 . . .. .
.: .
amino and R5 and R6 are independently selected from hydrogen, hydroxy amino or halo;
.~.. ....

-6~
;~'"`~' '.' 4S~5 e) a group1~ ~CH2)p- wherein ;~ is an integer . .
from 1 to 3;
S

D is the group\ / 3 ;
C\ :

¦ CH3 CH
/ \ COOM `

.
or the group C~2 ~C Ch2-X

COOM

in which the carbon atom bearing the C00M group is linked to the nitrogen ` -atom of the ~-lactame ring and M and X are as above defined, ~lth a molar -excess of an oxalyl:halide of formula halCOCOhal, wherein hal represents a .
halogen atom, in an organic solvent, in the presence of an acid binding agent, at a temperature from about -10 to about -60C, whereby the -COOM group is transformed into the group COO-COCOhal in which hal is as above defined, treating the obtained compound with a halogenating agent.at a temperature .:
from about -30 to about -S0C, ln the presence of an acid blnding agent and subsequently with a ~CI 4) alkyl orthoformate or an alcohol selected from tCI 4~ aIkanols, phenyl ~Cl 4) alkanols, tc5 7) cycloalkanols and~C2 8) alkanediols, at a temperature of about -30 to 50C, in the presence of an :
acid blnding agent, and hydroliæing the obtained iminoether in a mixture o~
water and a tci 4) alkanol, at a temperature o~ about _5 to la~c, at an acidic pN between about 3 and abeut 5 and ~here requ~red~react~ng the thus ~ -:

~;
' :, ' ~s~s produced compounds with a base to produce a suitable salt thereof.
With the term "protected amino group~ it is intended an aminic func-tion protected by a group which is not affected by the described reaction con-ditions which are employed for splitting the moiety R-CO. Examples of protect-ing groups are acyl radicals deriving from mono-or di-carboxylic acids of 2 to j:
8 carbon atoms optionally substituted with halogen atoms, benzoyl, phenyl and -~
benzoyl carrying 1 to 3 substituents independen~ly ~elected from halo, nitro :
and cyano, phenacetyl, benzyloxycarbonyl, tertbutoxycarbonyl, ~C5 7) cyclo-alkyloxy carbonyl, benzenesulfonyld tolueneisulfonyl, phenacylsulfonyl, a group ~:~
representable by the formula R2-Z-C- wherein Z is O or NH and R2 is ~Cl 6) alkyl or the group `
(CH2)n ~ R3 where _ is an integer from O to 6 and R3 and R~ independently represent hydro-gen, halogen, nitro, ~Cl 6) alkyl, (Cl 6~ alkox~. :.j .
When Y in the groups S-Y and S-C-Y as deflned above) is a 5-7 membered ; ;. .:
hetrocyclic ring it may be chosen from the group conslsting of 1, 3, 4-thia-' ~:
: ';' ;'': ' '" "' -7a- ::

.

~)45~15 diazole, 1, 2, 4-thiadiazole, 1~ 2, 5-thiadiazole, 1, 3, 4-oxadiazole, 1~ 2~ 4-oxadiazole, 1, 2, 5-oxadiazole, 1, 2, 4-triazole, 1, 2, 3-triazole, tetrazole, pyridine, pyridazine, pyrimidine and pyrazine.
The process of the invention, which in its main aspects is carried out at a temperature between _10 and_60C comprises as the first and inventive step the protection of the carboxylic group on the heterocyclic portion o~
the compounds of formula I, II and III by reacting the selected compound with an oxalyl halide such as for instance,oxalyl chloride or oxalyl bromide, oxalyl chloride being the more preferred. Accordingly, the group COOM is 10 readily transformed into the corresponding group COO-COCOhal, wherein hal -stands for a halogen atom~ The use o~ oxalyl chloride as protecting agent of the carboxy group is not known from the chemical literature: it is rather described and employed as halogenating agent, see for instance C.F. Murphy and R~ B. Koehler, Jour. Org. Chem. 35, 2429~ 1970, where it is said that oxalyl chloride displays its chlorinating action at a temperature of o_lo&.
On the contrary, we have surprisingly found that by operating within the t~mperature range of from about _10 to -60C, oxalyl chloride may act as a protecting agent without any chlorinating effect on ~he reaction substrate.
After protection of the group, the removal of the R-COiradical is performed as described in the art, 1.e. the selected substrate is treated with a halogenating agent, such as, for instance, phosphorus pentahalides, to obtain the corresponding iminohalide which is in turn reacted with an app~o-priate alcohol to give an iminoether: the iminoether is then hydrolized according to the known procedures for hydrolizing said classes of substances. ~
During this last reaction step also the hydrol~sis of the group i ~ -,~: --COO-COCOhal takes placeg so that 6-aminopenicillanic acid or 7-aminocephalos poranic aoid or its derivatives with Yarious substituents at the 3-po~ition are p~actically recovered directly from the reaction maxture in almost quantitative yields.

A process according to the present invention, in as when the carboxy - , ~4S~5 group is pro~ected as a silyl ester, the free carboxy group is restored simultaneously with the hydrolysis of the intermedlate lminoether, substan-tlally accordlng to Belgian Patent 628,494. Howe~er it must be pointed out that oxal~l halides, unlike haloalkylsilanes, alkylsilazanes and analogous derivatives, are very cheap commercially available products, are easy to handle and offer considerably reduced risk of causing harm to technicians or workers.
Furthermore, oxalyl halides remarkably shor~en the times of the entire process: in fact, the protection of the carboxy group takes place at about the same temperature of the subsequent steps, while the formation of the silyl esters occurs at room temperature, and a drastic cooling of the reaction mixture is required to perform the subsequent reactions. Finally, the processes of this invention can advantageously be carried out on a great variety of starting substrates. These and other advantages which will be apparent from a more detailed description of the invention make the process herein described which is particularly suited to be applied on an industrial ``
scale, as the overall yields of 6-aminopenicillanic acid, 7-aminocephalospor-anic acid or its derlvatives at the 3-positlon with various substituents are generally greater than 95%.
According to a preferred mode of carr~ing out the process of the invention, the selected substrate or an acid salt thereof is dissolved or suspended in an organic solvent such as, for instance, dlethyl e~her, nitro- -methane, halog~nated hydrocarbons containing from 1 to 4 carbon atoms ~methylene chloride and chloroform are the mos~ preferred ones), in the :
presence of an acid binding agent, which is suitably selected from tertiary organic bases, e.g. tri-(Cl 4) alkylamines, N,N-dimethylaniline, quinoline, pyridine, lutidine, picoline and analogs. The presence of the acid binding agent is required both for blocking the acid which derives from the selec~ed substrate if this is used as an acid addition salt, and for binding the hydro-halogenic acid which forms the subsequent s~ep co~cerned ~lth the protection :, , of the carboxy group by means o oxal~l halides. This step is carried out by ,, . ._ 9-11)4511S -rapidly cooling the resulting solution to about -40C and then adding a molar excess over the starting substrates of the selected oxal~l halide; preferably oxalyl chloride. The amount of the oxalyl halide which is added chiefly depends on the selected starting substrate, since it may contain other func-tlons which must bs protected in order to avoid undesirable side-reactions:
these functions are for instance represented by hydroxy~ amino, sulfhydryl or even by another carboxy group when a compound is selected where R is the radical MOOC ~ H-~CH2)3, wherein M and R1 are defined as above.
Under the employed reaction conditions oxalyl halides prove to be excellent protective groups also for the above cited functi~ns, which are easily restored at the end of the process simultaneously with the carboxy group. The amount of oxalyl halide which is added is about 2-10 times the molar amount of the selected starting substrate.
The two reactants are allowed to contact for 25-40 minutes at a temperature comprised between -10 and -60C, preferably between -30 and 45C, then the reaction mixture is submitted to the reaction conditions for cleaving the amidic bond. ~
This procedure comprises as the first step the reaction with a , halogenating agent, at about -30 and -50C~ for one-two h~urs in the presence of an acid binding agent9 which is defined as above. Examples of halogenating ~; .. . . .
agents which can advantageously be employed are phosphorus pentachloride, phosphorus pentabromide, thionyl chloride, phosphorus tribromide, phosphorus . .
oxychloride, phosgene, p-toluenesulfonylchloride. Accordingly, the amidic group of the selected starting compound of formula I II and III is converted into an iminohalide group, which is~i~ turn transformed into the corresponding iminoether by reaction at a temperature between -35 and -50C with an appropriate pr~mary or secondary alcohol or a (C1_4) alk~l orthoformate, Examp1es of alcohols which can suitably be used are represented by ~C1_ alkanols, such as, for instance, methanol, ethanol, propanol~ isopropanol~ -butanol or isobutanol, phenyl (Cl_4) alkanols, e.g. benzyl alcohol, (C5 7 --10_ , .

- - `

~4S~L15 :
cycloalkanols as, for example, cyclohexanol, or (C2_8) alkanediols, e.g.
ethylene glycol, 1,6-hexane-diol and analogs. When an orthoformate is used, it is generally eth~l orthoformate.
Also this step requires to be carried out in the presence of an acid binding agent, which is defined as above. The obtained iminoethers are then poured into a mixture of water/(Cl_4) alkanols and the resulting solution is allowed to stand for about nine-fourteen hours at a temperature between -5 and 10C. A highly pure crystalline precipitate forms which is recovered by filtration. The compound so obtained, depending on the starting substrate, is 5-aminopenicillanic acid, 7-i~minocephalosporanic acid or a derivative at the 3-position of 7-aminocephalosporanic acid. These compounds are recovered ~ -in almost quantitative overall yields, in any case never lower than 95%. The following examples are provided with the purpose of better illustrating the preferred modes of performing the invention, but are not intended to establish -any upper limit to the in~ention itself.
Exd=~le 1 1 Gram (0.00177 mole) of-N-(p-nitrobenzoyl)-cephalosporin C is suspended in lS ml. of methylene chloride containing 0.25 ml. of triethyIamine, to which are added 0.45 ml. of N,N-dimethylaniline. The resulting solution is cooled to -40C, then 1.5 ~l. tO.0171 mole) of oxalyl chloride are added dropwise and the resulting mixture is allowed to stand at about -40C for 30 minutes. After adding 890 mg. of phosphorus pentachloride and 1.1 ml. of N,N~dimethylaniline, the solution is cooled to about -60C, added with 9.5 ml9 :: , (~0.0985 mole) of freshly distilled butanol containing 0.2 ml.o~ N~N-di~ethy-laniline an~ kept for 90 minutes at ~40C. The reaction mixture is poured . ~ . .
into a mixture of 9 ml. of water and 4.5 m1. of ethanol~ then the pN of the ; -resulting solu~ion lS brought from the initial value of 0.5 to 3-5 upon adding aqueous 20~ammoniium hydroxide. Upon stan~ing overnight at 0-5C a ~ -~
crystalline product separates whioh is filte~ed, washed with ~ethanol and acetone and dried. Yield: 0.471 g.(98~2%) of 7-aminocephalosporanic acid, , ~ ,.,'.';

, : .
: .......

~L(945~Li5 Example 2 The process descri,bed in Example 1 was carried out with cephalospo-rin C directly isolated from the fermentation broth as N-(p-nitrobenzoate) having a purity degree of 80%. Starting from 1 g. of N-(p-nitrobenzo~l)-cephalosporin C of the indicated purity 0.367 g. (95%) of 7_aminocephalos_ poranic acid are obtained.
E~ample 3 The process of Example 1, was repeated starting with lD6-g. (0.00282 mole) of N-(p-nitrobenzoyl)-cephalosporin C and employing 0.00855 mole of oxalyl chloride, 0.743 g. (97O of 7-a~inocephalosporanic acid are obtained. ' ,-~ ~': .,''.
1 Gram of N~(p-nitrobenzoyl)-cephalosporin C with a degree of purity of 80% is treated with ~0171 mole of oxalyl chloride and phosphorus penta-chloride as described in Example 1. The reaction mixture is then treated at about -40C with 4 ml. of eth~l,orthoformate containing catalytic amount ''~
of aqueous 20% hydrochloric acid instead of butanol and kept at the same temperature for~80-100 minutes.~ The recovery of the final product is'again ', carried out as in Example 1. Yield 0.375 gO (97.5) of 7-aminocephalosporanic acid. , ~ Example 5 The process of Example 1 is repeated star,ting,with 0.91S g. (0.00191 le)~of,cepha1Osporin,C zinc salt. The 7-aminocephalosporanic acid is re- ; ", ' covered in almost quantitative yields. , ,~ ' ', ; The procedure of Example;1 is repeated starting with 0.930 g. ' (0,00179 nole) of N-benzoylcephalosporin C. Yield: 0~466 g. (96%~ of ~
7-aminocephlaosporanic acidO ~' ' Examp1e ?~ ' '"
The procedure of Example~1 is repeated by- using as th~ substrate 1.09 g. ~0.00178 mole) of N-(p~nitroben~o~l)-cephalosporin C disodium salt~

~" ;~

1~45~15 Yield: 0.490 g. (almost quantitative yie:Ld) of 7-aminocephalosporanic acid.
Example 8 The procedure of Example 1 is repeated starting with 1.65 g.
(0.00221 mole) of N-(p-nitrobenzo~ cephE~losporin C di-cyclohexylamine salt.
Yield: 0.578 g.~(96.5%) of 7-aminocephalosporanic acid.
Exam~e 9 The procedure of Example 1 is repeated starting with 2 g. (0.00562 mole) of benzylpenicillin sodium salt. Yield: 1~178 g. (970 of 6-amino~
penicillanic acid.

."

: ' ,. .
~ ,. . .
.'. " ': '.

.

, .
. - .

'`, " ' ' : ': ~ . :, . .

' ;'.
' ' . ' ., ':: ' ......
'. '', ':' ,:
, . . . . .
. ~ ... .
'' '" "''''' ""'' ,.

~13_ ~
... . .. .

-:~ ';,"

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing 6-aminopenicillanic acid, 7-aminocephalos-poranic aeid and derivatives at the 3-position of 7-aminocephalosporanic acid, and base addition salts thereof of the general formula I

wherein D1 may be the group or the group in which the carbon atom bearing the carboxy group is linked to the nitrogen atom of the .beta. -lactam ring, and M represents hydrogen, or metal or ammonium cations, X represents hydrogen, hydroxy, sulfhydryl, halo, azido, cyano, (C1-6) alkoxy, (C2-6) alkanoyloxy, carbamoyloxy, (C1-6) alkylcarbamoyloxy, aryloxy, aralkyloxy, aroyloxy, arylalkanoyloxy wherein the aromatic portion is represented by a phenyl or naphthyl radical optionally substituted with (C1-4) alkyl, (C1-4) alkoxy, halo and nitro groups and the alkyl or alkanoyl portions contain from 1 to 4 carbon atoms, tri-(C1-4)-alkylammonio, pyridinio, (C1-4) alkyl substituted pyridinio, a group -S-Y or wherein Y repres-ents (C1-6) alkyl, (C2-6) alkanoyl, aryl and aralkyl as above defined, a 5-7 membered heterocyclic ring containing O, N and S and optionally substitu-ted with (C1-4) alkyl, hydroxy, hydroxy (C1-4) alkyl or trifluoromethyl, which comprises reacting a molar proportion of a substrate of the general formula II

or an acid salt thereof, wherein R is selected from:
a) an alkyl group of 2 to 8 carbon atoms;
b) a group , wherein M is defined as above and R1 is hydrogen, amino or a protected amino group, c) a group wherein W represents O, S or a carbon-carbon bond, and m is an integer from 0 to 3, with the proviso that when W is oxygen or sulfur, m is different from zero;
d) a group wherein Q stands for hydrogen, hydroxy or amino and R5 and R6 are independently selected from hydrogen, hydroxy, amino or halo:
e) a group wherein p is an integer from 1 to 3;

D is the group or the group in which the carbon atom bearing the COOM group is linked to the nitrogen atom of the .beta.-lactam ring and M and X are as above defined, with a molar excess of an oxalyl halide of formula halCOCOhal, wherein hal represents a halogen atom, in an organic solvent, in the presence of an acid binding agent, at a temperature from about -10 to about -60°C, whereby the -COOM
group is transformed into the group COO-COCOhal in which hal is as above defined, treating the obtained compound with a halogenating agent at a tem-perature from about -30 to about -50°C, in the presence of an acid binding agent and subsequently with a (C1-4) alkyl orthoformate or an alcohol selected from (C1-4) alkanols, phenyl (C1-4) alkanols, (C5-7) cycloalkanols and (C2-8) alkanediols, at a temperature of about -30 to 50°C, in the presence of an acid binding agent and hydrolizing the obtained iminoether in a mixture of water and a (C1-4) alkanol, at a temperature of about -5 to 10°C, at an acidic pH between about 3 and about 5 and where required reacting the thus produced compounds with a base to produce a suitable salt thereof.

2. A process according to Claim 1 in a compound of formula I, as defined in Claim 1, the group Y is selected from the group consisting of thiazole, isothiazole, oxazole, isooxazole, 1, 3, 4-thiadiazole, 1, 2, 4-thiadiazole, 1, 2, 5-thiadiazole, 1, 3, 4-oxadiazole, 1, 2, 4-oxadiazole, 1, 2, 5-oxadiazole, 1, 2, 4-triazole, 1, 2, 3-triazole, tetrazole, pyridine, pyridazine, pyrimidine and pyrazine.

3. A process according to Claim 1 wherein the compound of formula II, as defined in claim 1, is reacted with a molar excess of an oxalyl halide for 25 - 40 minutes.

4. A process according to claim 1 wherein the halogenating agent is selected from the group consisting of phosphorous pentachloride, phosphorus pentabromide, thionyl chloride, phosphorus tribromide, phosphorus oxychloride, phosgene and p-toluenesulfonylchloride.

5. A process according to claim 1 wherein said halogenating agent is reacted with the product resulting from the reaction of the compound of formula II, as defined in claim 1, and said oxalyl halide, for one to two hours.

6. A process according to claim 1 wherein said iminoether is hydrolysed in water and a (C1-4) alkanol for about 9 to fourteen hours.

7. A process as in claim 1, Wherein, when R is the radical M is as defined in claim 1 and R1 is a protected amino group, the protecting group of the amino function is selected from acyl radicals deriving from mono- or di-carboxylic acids of 2 to 8 carbon atoms optionally substituted with halogen atoms, benzoyl, phenyl and benzoyl carrying 1 to 3 substituents independently selected from halo, nitro and cyano, phenacetyl, benzyloxycar-bonyl, tertbutoxycarbonyl, (C5-7) cycloalkyloxy carbonyl, benzenesulfonyl, toluenesulfonyl, phenacylsulfonyl, a group representable by the formula wherein Z is 0 or NH and R2 is (C1-6) alkyl or the group where n is an integer from 0 to 6 and R3 and R4 independently represent hydro-gen, halogen, nitro, (C1-6) alkyl, (C1-6) alkoxy.

8. A process as in claim 1, wherein from about 2 to about 10 molar equivalents of the oxyalyl halide are employed for each molar equivalent of the compound of formula II.

9. A process as in claim 8, wherein the oxyalyl halide is oxalyl choride.

10. A process as in claim 1, wherein the organic solvent is a lower halo-genated hydrocarbon.

11. A process as in claim 10, wherein the lower halogenated hydrocarbon is methylene chloride.

12. A process as in claim 1, wherein the acid binding agent is a (C1-4) alkylamine, N,N-dimethylaniline or a mixture thereof.

13. A process as in claim 1, wherein the reaction between the oxalyl halide and the substrate of formula II is carried out at a temperature com-prised between about -35 and about -45°C.

14. A process as in claim 1, wherein the halogenating agent is phosphorus pentachloride.

15. A process as in claim 1, wherein the (C1-4) alkyl-orthoformate is ethyl-orthoformate.

16. A process as in claim 1, wherein the employed alcohol is an aliphatic alcohol containing from 1 to 4 carbon atoms.

17. A process as in claim 16, wherein the aliphatic alcohol is butanol.

18. A process for preparing a compound of formula wherein X is defined as in claim 1, which comprises reacting a molar amount of a substrate of formula or an acid salt thereof, wherein R, X and M are defined as in Claim 1, with 2-10 molar equivalents of oxalyl chloride, in methylene chloride, in the presence of a mixture of triethylamine and N,N-dimethylaniline at a tempera-ture comprised between about -35 and-45°C, for 25-40 minutes, treating the obtained product with phosphorus pentachloride at a temperature between about -30 and about -50°C in the presence of N,N-dimethylaniline for one-two hours and subsequently with an agent selected from ethyl orthoformate and butanol at a temperature comprised between about -30 and about -50°C, in the presence of N,N-dimethylaniline, and hydrolizing the obtained imino-ether in a mixture of water and ethanol, for about 9 to about 14 hours, at a temperature between about -5 and about 10°C, at an acidic pH comprised bet-ween about 3 to about 5.

19. A process as in Claim 12, whereby 6-aminopenicillanic acid of formula is prepared starting from a substrate of formula or an acid salt thereof, wherein R and M are as above defined.